Cu-mediated enantioselective C–H alkynylation of ferrocenes with chiral BINOL ligands

A wide range of Cu(II)-catalyzed C–H activation reactions have been realized since 2006, however, whether a C–H metalation mechanism similar to Pd(II)-catalyzed C–H activation reaction is operating remains an open question. To address this question and ultimately develop ligand accelerated Cu(II)-catalyzed C–H activation reactions, realizing the enantioselective version and investigating the mechanism is critically important. With a modified chiral BINOL ligand, we report the first example of Cu-mediated enantioselective C–H activation reaction for the construction of planar chiral ferrocenes with high yields and stereoinduction. The key to the success of this reaction is the discovery of a ligand acceleration effect with the BINOL-based diol ligand in the directed Cu-catalyzed C–H alkynylation of ferrocene derivatives bearing an oxazoline-aniline directing group. This transformation is compatible with terminal aryl and alkyl alkynes, which are incompatible with Pd-catalyzed C–H activation reactions. This finding provides an invaluable mechanistic information in determining whether Cu(II) cleaves C–H bonds via CMD pathway in analogous manner to Pd(II) catalysts.

Given the aforementioned advantages of Cu-catalyzed C−H activation reactions, our group has devoted extensive effort to the development of Cu catalysis since the first report in 2006 34 .We have developed diverse transformations using a wide range of coupling partners enabled by our class of practical oxazoline-aniline directing groups (DGs) [46][47][48][49][50][51][52][53][54] .Our oxazoline-aniline DG not only unlocks reactivity with an enormous range of coupling partners for C-H activation, including free amines/amides 46 and trifluoromethylating reagents 48 but also demonstrates exceptional tolerance for otherwise challenging functional groups, especially a broad range of heterocycles 52,53 .
In the realm of stereoselective Cu-catalyzed C−H activation, we recently reported the diastereoselective C-H thiolation of ferrocenes using a chiral oxazoline directing group (Fig. 1a) 55 .Despite its practical limitations, this chiral auxiliary approach represents a promising lead for the ultimate development of Cu-catalyzed enantioselective C−H activation reactions.Here, we report the discovery of BINOL-derived ligands that accelerate the Cu-mediated C-H alkynylation of ferrocenes with an oxazoline-amide directing group.When using (S)−6,6'dibromo-BINOL as the chiral ligand, the Cu-mediated enantioselective C-H alkynylation of ferrocene carboxylic acid derivatives was achieved with high enantioselectivity (Fig. 1b).Mechanistic studies support the presence of ligand acceleration and indicate the acceleration occurs at the key C-H cleavage step of the catalytic cycle.
Planar chiral ferrocenes are prevalent in synthetic chemistry, materials science, and medicinal chemistry [66][67][68][69] , as well as privileged scaffolds for chiral ligands and catalysts [70][71][72][73][74][75] .More specifically, orthosubstituted planar chiral ferrocene carboxylic acids and their derivatives, the products of this method, are highly valuable in the preparation of chiral monodentate (carboxylates) 76 and bidentate (oxazolines/phosphines, etc.) 77 ligands.Traditional directed ortho lithiation approaches for the enantioselective preparation of orthosubstituted ferrocene carboxylic acids rely on chiral auxiliaries [78][79][80][81][82] .They suffer from efficiency and atom economy losses associated with the use of chiral auxiliaries, as well as the scope limitations associated with organolithium reagents.A Cu-catalyzed enantioselective C-H activation approach towards ortho-substituted planar ferrocene carboxylic acid derivatives would circumvent these limitations and permit direct installation of diverse functionality using an abundant base metal catalyst.Notably, very few enantioselective catalytic C-H activation reactions to prepare ortho-substituted ferrocene carboxylic acid derivatives are known 83 .
Preliminary experiments with the racemic Cu-mediated C-H alkynylation of ferrocene carboxylic acid substrate 1 with ethynylbenzene (2a) provided only 14% yield of product 3a under our previously developed conditions for Cu-mediated C-H alkynylation, which did not use an exogenous ligand 36 .Through a systematic evaluation of reaction parameters, the yield of 3a was improved to 56% (17/1.0mono/di).Encouraged by our success in developing ligands capable of accelerating Pd-catalyzed C−H activation, we then initiated a search for ligand acceleration effects for this Cu-mediated transformation.A range of ligand scaffolds were systematically investigated (Fig. 2, see Supplementary Information for more details).Common mono-and bi-dentate donating ligands such as triphenylphosphine (L1), BINAP (L2), 1,10-phenanthroline (L3), and bis-oxazoline (L4) either inhibited or showed no beneficial impact on reactivity.We next evaluated mono-protected amino acid (L5) and pyridone (L6) ligands, two scaffolds widely used in Pd-catalyzed C−H activation and capable of directly accelerating the key C−H activation step.Unfortunately, both ligand classes were ineffective in this transformation.Pyridinetype (L7) ligands, which are also widely used to improve the reactivity of Pd C−H activation catalysts, failed to show any improvement.Finally, mono-oxazoline ligands (L8), which are effective ligands in Cumediated C−H activations with monodentate directing groups 43 , were not beneficial in this transformation.
In contrast to the results with established ligands for Pd-catalyzed C−H activations, we found that (S)-BINOL (L10) showed a significant improvement in reactivity, increasing the yield of 3a to 69% and indicating the potential for ligand accelerated catalysis 84 .Other bisphenol scaffolds such as L9 and (S)-spirosilabiindane diol (SPSiOL, L12) 85 showed inferior results, while (S)-spirobiindane diol (SPINOL, L11) demonstrated similar reactivity as L10.Given the established modularity and ease of derivatization of the BINOL core, we chose the BINOL platform for further investigation.We first evaluated 3,3'-Me 2 -BINOL (L15), which to our delight gave an improved yield of 76% (4.8/1 mono/di).Control experiments revealed that both phenolic hydroxyl groups are crucial for the high reactivity (L13, L14 vs. L10).The observation of this potential ligand acceleration effect with Cu not only will promote the discovery of Cu-mediated/catalyzed C−H activations with this abundant and economical metal but also enable the development of enantioselective catalysis (vide infra).

Substrate scope for the Cu-mediated C-H alkynylation
With the optimal conditions in hand, the scope of the ligandaccelerated Cu-mediated C-H alkynylation was investigated.Employing ferrocene monocarboxylic acid-derived 1 as the model substrate, we first evaluated the breadth of terminal alkynes (Fig. 3).In general, this method could tolerate a series of aryl, alkenyl, and alkyl- substituted terminal alkynes, providing the desired products in moderate to good yields (3a-r).Both electron-rich (2b-d, 2g, 2i) and electron-deficient (2e, 2f, 2h, 2j) substituents on the phenyl group of phenylacetylenes are compatible with this protocol.To our delight, terminal alkyne 2l bearing a heterocyclic thiophene moiety was also compatible, providing product 3l in 64% yield.Notably, aliphatic alkynes containing both cyclic (2m, 2n) and acyclic (2o-q) alkyl groups, were all compatible, giving products 3m-q in good yields.Conjugated enyne 2r gave the ferrocene-containing enyne 3r in 62% yield, further demonstrating the generality of this protocol.
Next, the scope of ferrocene substrates was evaluated with phenylacetylene (2a) as the alkynylating reagent (5a-i), as presented in Fig. 4. Ferrocenes bearing both electron-deficient ketone and ester groups (4a-e) and electron-rich alkyl (4f-h) substituents on the lower cyclopentadiene ring were all tolerated, affording the corresponding alkynylated ferrocene derivatives in moderate to good yields.Bulky ferrocene 4i bearing a Cp* on the lower ring gave a lower yield (38%) with excellent mono selectivity, potentially due to steric hindrance.
To demonstrate the synthetic utility of the Cu-mediated asymmetric C-H alkynylation, we conducted the transformation on a gramscale and elaborated the product to synthetically useful compounds.First, the gram-scale reaction was conducted with 70 mol% of Cu(OAc) 2 , 20 mol% of CuOAc, and 20 mol% of (S)-L21 (Fig. 7a), providing enantioenriched mono-alkynylated product 3a in 52% yield with slightly lower enantioselectivity (90:10 er), and the di-product (di-3a) in 7% yield.Recrystallization from hexane/dichloroethane provided 3a in very high selectivity (99.5:0.5 er) and 38% yield.To explore potential applications of the product (Fig. 7b), we derivatized 3a through a synthetic sequence, first through hydrogenation to ortho-alkylated 6a, followed by removal of the directing group to reveal ferrocene carboxylic acid 7a, with minimal loss of enantioenrichment (98:2 er).Ortho-substituted planar chiral ferrocene carboxylic acids have recently been shown by Matsunaga to be effective chiral ligands in Co-catalyzed enantioselective C(sp 3 )-H activation reactions 76 .As a demonstration of our method's potential impact, we employed 7a as a chiral ligand in the Co-catalyzed C(sp 3 )-H amidation of thioamide 8 (Fig. 7b), providing product 10 in high yield (95%) and promising enantioselectivity (70.5:29.5 er).This example highlights the synthetic utility of our Cu-mediated enantioselective C-H alkynylation, which enables access to novel chemical space in valuable ortho-substituted planar chiral ferrocenes.

Mechanistic insights
The increased reactivity and high enantioselectivity imparted by the BINOL ligands were suggestive of ligand-accelerated catalysis, particularly in light of the strong background reaction.To further probe the possibility of ligand acceleration and collect data on the catalytic cycle, we then conducted some preliminary mechanistic studies on the system.We first performed a one-pot intermolecular competition kinetic isotope effect (KIE) experiment using 1a and ortho-deuterated D 2 −1a (Fig. 8a) in the presence of L21.A primary KIE was observed (4.9), indicating that C-H cleavage is likely the rate-determining step.This result indicates that the Cu-mediated C-H alkynylation is likely proceeding through CMD C-H activation at Cu, as opposed to SET pathways that do not involve Cu in C-H bond breaking, which would show no KIE (~1) 86 .This is a critical mechanistic insight as it both establishes that Cu cleaves C-H bonds in a similar manner as Pd and suggests a plausible mechanism for ligand involvement and acceleration.Having identified C-H cleavage at Cu as the rate-determining step, we next conducted initial rate studies to test for ligand acceleration (Fig. 8b).We observed a striking initial rate difference when comparing catalyst reactivity with and without BINOL-derived ligand (S)-L21.A rate acceleration of 11.6 times was observed with (S)-L21, strongly      In conclusion, Cu-mediated enantioselective ortho C-H alkynylation of ferrocene carboxylic acid derivatives has been realized using a chiral BINOL-derived diol ligand.This scaffold demonstrates ligandaccelerated catalysis with the Cu-mediated C-H activation, which both boosts the reactivity and also enables enantioselective catalysis.The development of additional Cu-catalyzed/mediated asymmetric C-H activation reactions with these chiral diol ligands is an ongoing research direction in our laboratory.

Methods
General procedure for Cu-mediated asymmetric C-H alkynylation of ferrocenes A 15 mL scale tube was charged with substrate 1 or 4 (0.1 mmol, 1.0 equiv.),Cu(OAc) 2 (12.7 mg, 0.07 mmol), CuOAc (3.7 mg, 0.03 mmol), (S)-L21 (13.3 mg, 30 mol%), Ag 2 CO 3 (13.8mg, 0.05 mmol), NaOAc (8.2 mg, 0.1 mmol), 2 (0.25 mmol, 2.5 equiv.),DMSO (5.0 mL) under air atmosphere.The tube was capped tightly, and the reaction mixture was stirred at room temperature for 30 s and then stirred at 60 °C for another 12 h.Upon completion, the reaction was cooled to room temperature, and then EtOAc was added to dilute the reaction mixture.The organic layer was washed with NH 3 •H 2 O, saturated brine, and dried over Na 2 SO 4 .Volatiles were removed under a vacuum.The crude product was purified by column chromatography to afford the desired product (R p )-3 or (R p )-5.The ratio of mono/di was determined by the analysis of crude 1 H NMR. Full experimental details and characterization of new compounds can be found in the Supplementary Methods.

Fig. 7 |
Fig. 7 | Gram-scale reaction, product elaboration, and synthetic application.a Gram-scale reaction.b Product elaboration and synthetic application in catalysis.

Fig. 8 |
Fig. 8 | Mechanistic studies.a Kinetic isotope effect experiments.b Initial reaction rate in comparison with and without (S)-L21.